Synthesis of C(sp2)-P bonds by palladium-catalyzed reactions Mechanistic investigations and synthetic studies

Abstract: This thesis focuses on synthetic and mechanistic aspects of palladium-catalyzed C(sp2)-P bond-forming reactions, with the aim to develop mild and efficient methods for the synthesis of biologically active phosphorus compounds, e.g. DNA analogs.The first part of the thesis is devoted to detailed mechanistic investigations of the palladium-catalyzed C-P cross-coupling reaction, in order to fully understand the underlying chemistry and by rational design of the reaction conditions, improve the overall efficiency of the process and broaden its applicability. In particular influence of palladium coordination by different anions on the rate of ligand substitution and reductive elimination steps of the reaction was studied. It was found that coordination of acetate ion results in unprecedented acceleration of both of the mechanistic steps, what leads to remarkable shortening of the overall reaction times. In-depth kinetic investigations enabled to ascribe the observed effects to ability of the acetate ion to act as a bidentate ligand for palladium. This causes considerable alternation of the reaction mechanism, comparing to the reaction involving halide-containing complexes, and results in significant rate increase.Based on the above mechanistic studies an efficient method for the synthesis of arylphosphonates, using substoichiometric amounts of inorganic acetate additive and reduced amount of catalyst, was developed.In the next part of the thesis, efforts to further enhance the palladium-catalyzed cross-coupling efficiency by using a microwave-assisted synthesis are described. These explorations resulted in a successful development of two protocols, one for a cross-coupling of H-phosphonates and the other for H,H-phosphinates, under the microwave heating conditions. Application of this energy source resulted in extremely short reaction times, measured in minutes.The final chapter of this thesis deals with studies on palladium-catalyzed SN2’ propargylic substitution reaction with phosphorus nucleophiles, which leads to allene products. Efficient procedure for the synthesis of allenylphosphonates and related compounds was developed. The method enables full control of stereochemistry in the allene moiety and at the asymmetric phosphorus center. Some conclusions on the mechanism of the reaction were also drawn.